GA&HA-Modified Liposomes for Co-Delivery of Aprepitant and Curcumin to Inhibit Drug-Resistance and Metastasis of Hepatocellular Carcinoma

Abstract

Background Tumor microenvironment (TME) plays a vital role in the development of hepatocellular carcinoma (HCC). Mounting evidence indicates that peripheral nerves could induce a shift from quiescent hepatic stellate cells (HSCs) to cancer-associated fibroblasts (CAFs) by secreting substance P (SP). The anti-tumor strategy by targeting “SP-HSCs-HCC” axis might be an effective therapy to inhibit tumor growth and metastasis. Objective In this study, we prepared novel liposomes (CUR-APR/HA&GA-LPs) modified with hyaluronic acid (HA) and glycyrrhetinic acid (GA) for co-delivery aprepitant (APR) and curcumin (CUR), in which APR was chosen to inhibit the activation of HSCs by blocking SP/neurokinin-1 receptor (NK-1R), and CUR was used to induce apoptosis of tumor cells. Results To mimic the TME, we established “SP+HSCs+HCC” co-cultured cell model in vitro. The results showed that CUR-APR/HA&GA-LPs could be taken up by CAFs and HCC simultaneously, and inhibit tumor cell migration. Meanwhile, the “SP+m-HSCs+HCC” co-implanted mice model was established to evaluate the anti-tumor effect in vivo. The results showed that CUR-APR/HA&GA-LPs could inhibit tumor proliferation and metastasis, and reduce extracellular matrix (ECM) deposition and tumor angiogenesis, indicating a superior anti-HCC effect. Conclusion Overall, the combination therapy based on HA&GA-LPs could be a potential nano-sized formulation for anti-HCC therapy.

Multifunctional and stimuli-responsive liposomes in hepatocellular carcinoma diagnosis and therapy

“…In this line, liposomes were modified with glycyrrhetinic acid (GA) and HA to co-deliver aprepitant and curcumin. Such drug-loaded liposomes showed uptake by HCC cells and cancer-associatd fibroblasts that suppressed tumorigenesis in vitro and in vivo, and disrupted the invasion [217] . In another effort, GA/HA-functionalized liposomes were utilized to co-deliver berberine and curcumin that were able to stimulate apoptosis in tumor cells and impair their proliferation [110] .…”

Critical Review in Designing Plant-Based Anticancer Nanoparticles against Hepatocellular Carcinoma

“…While niosomes have been preferred to conventional liposomes due to their improved stability, nanoliposomes offer cell-targeting abilities. For example, Tian et al recently surface modified nanoliposomes with hyaluronic acid and glycyrrhetinic acid for the delivery of curcumin to HCC cells and hepatic stellate cells at the same time; the nanoliposome could significantly inhibit metastasis and initiate tumor microenvironment remodeling [ 168 ]. Such strategies have been demonstrated to be useful, especially for targeting a heterogeneous population of cancer cells that tend to cause drug resistance.…”

Lipid Nanoparticles-Based Therapy in Liver Metastasis Management: From Tumor Cell-Directed Strategy to Liver Microenvironment-Directed Strategy

“…Besides CAP/GA-sHA-DOX, some other active-targeting LNPs have also been fabricated to inhibit the crosstalk between HSCs and tumor cells. One dual-targeting strategy generated by Li et al 93 and Qi et al 94 used aprepitant to block the activation of HSCs while using co-delivered curcumin to induce tumor cell apoptosis. Both in vitro and in vivo experiments demonstrated that these dual-targeting LNPs would successfully inhibit the growth of tumor cells and reverse the chemotherapy resistance in the liver by blocking the HSC-tumor cell interaction.…”